2. Academic Validation
  3. The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin

The serine protease hepsin mediates urinary secretion and polymerisation of Zona Pellucida domain protein uromodulin

  • Elife. 2015 Dec 17;4:e08887. doi: 10.7554/eLife.08887.
Martina Brunati 1,  Simone Perucca 1,  Ling Han 2,  Angela Cattaneo 3 4,  Francesco Consolato 1,  Annapaola Andolfo 4,  Céline Schaeffer 1,  Eric Olinger 5,  Jianhao Peng 6,  Sara Santambrogio 1,  Romain Perrier 7,  Shuo Li 6,  Marcel Bokhove 2,  Angela Bachi 3 4,  Edith Hummler 7,  Olivier Devuyst 5,  Qingyu Wu 6,  Luca Jovine 2,  Luca Rampoldi 1
Affiliations

Affiliations

  • 1 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
  • 2 Department of Biosciences and Nutrition & Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
  • 3 Functional Proteomics, FIRC Institute of Molecular Oncology, Milan, Italy.
  • 4 Protein Microsequencing Facility, San Raffaele Scientific Institute, Milan, Italy.
  • 5 Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
  • 6 Department of Molecular Cardiology, Lerner Research Institute, Cleveland, United States.
  • 7 Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
PMID: 26673890 DOI: 10.7554/eLife.08887
Abstract

Uromodulin is the most abundant protein in the urine. It is exclusively produced by renal epithelial cells and it plays key roles in kidney function and disease. Uromodulin mainly exerts its function as an extracellular matrix whose assembly depends on a conserved, specific proteolytic cleavage leading to conformational activation of a Zona Pellucida (ZP) polymerisation domain. Through a comprehensive approach, including extensive characterisation of uromodulin processing in cellular models and in specific knock-out mice, we demonstrate that the membrane-bound serine protease hepsin is the Enzyme responsible for the physiological cleavage of uromodulin. Our findings define a key aspect of uromodulin biology and identify the first in vivo substrate of hepsin. The identification of hepsin as the first protease involved in the release of a ZP domain protein is likely relevant for Other members of this protein family, including several extracellular proteins, as egg coat proteins and inner ear tectorins.

Keywords

Hepsin; Serine protease; Uromodulin; Zona Pellucida domain; biochemistry; cell biology; mouse.

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